[unreadable] [unreadable] Chronic obstructive lung disease (COPD), a leading cause of pulmonary disability and death, is caused mainly by cigarette smoking. The initial pathologic changes are in the small airways and central lobular alveoli, with chronic inflammation and concomitant local expression of protease, oxidant, apoptotic and other inflammatory mediators capable of injuring the airways and alveoli. The theme underlying the Weill Cornell COPD SCCOR is that the clinical phenotype of COPD evolves when the regenerative process of the lung are no longer capable of maintaining normal lung structure and.function under the persistent injury to airways/alveoli caused by smoking and the inflammatory host response to smoking. With this theme, the proposed SCCOR has 5 projects supported by 6 cores. Four projects are clinical (Projects 1, 2, 4, 5), all focused on gene expression of specific components of the lung in patients with COPD. One project is pre-clinical (Project 3), focused on lung regeneration. Cores A, B provide services to support the study of human subjects, Cores C, D provide services for analysis of biologic materials, Core E is focused on education for developing clinical research skills, and Core F provides administrative support. All of the projects use novel strategies to assess the underlying theme. Project 1, based on the clinical observation that smokers that are HIV-1+ have a high incidence of emphysema at an early age and limited smoking history, proposes to study gene expression in alveolar macrophages to help understand which mediators are the most important in mediating lung destruction. Project 2 exploits the knowledge from studies of Drosophila and the developing murine embryo that the Notch pathway is a "gatekeeper" for differentiation to help unravel the abnormal pattern of differentiation observed in the airway epithelium in COPD. Project 3 applies to the murine model of rapid postpneumonectomy lung regeneration to decipher the role of CXCR4+VEGFR1 + hemangiogenic precursor to lung revascularization. Project 4 studies genes used for ciliogenesis in the steady state and over time after wounding-induced airway epithelial regeneration to assess the role of deranged gene expression in abnormal cilia function in COPD. Project 5 utilizes a newly developed strategy to repetitively sample the human small airway epithelium to define abnormal expression of multiple categories of genes implicated in the pathogenesis of COPD, and uses this abnormal "small airway molecular signature" to assess the impact of smoking cessation, aerosol corticosteroid therapy, or leukotriene pathway inhibitor therapy on molecular pathways relevant to COPD. [unreadable] [unreadable] INDIVIDUAL PROJECTS AND CORE UNITS [unreadable] [unreadable] [unreadable] PROJECT 1: Role of Alveolar Macrophages in the Accelerated Emphysema [unreadable] Of HIV-1 Positive Cigarette Smokers [unreadable] (Kaner, Robert) [unreadable] [unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] With the advent of highly active antiretroviral therapy (HAART), the survival of individuals infected with HIV-1 has dramatically improved. However, recent recognition of the markedly accelerated development of emphysema in this population at an early age and with a minimal smoking history provides an opportunity to study the molecular basis for this problem. In this context, the emphysema of HIV-1/AIDS joins a1-antitrypsin deficiency as a clinical model of an accelerated form of lung destruction, and thus HIV-1 + individuals that smoke can serve as a model to understand the pathogenesis of emphysema. Based on the knowledge that the alveolar macrophage (AM) is the primary cell type of the lung that is chronically infected by HIV-1, and that the AM plays a central role in releasing mediators that mediate the lung destruction in smoking-ind.uced emphysema, we hypothesize that HIV-1 and cigarette smoke synergize to activate AM to express a transcriptome that is highly dangerous to the lung parenchyma. Its evaluation will help to identify the activation pathways that are most critical in the development of emphysema and represent pharmacologic targets. Based on this background, we propose to assess 3 specific aims. Aim 1. To test the hypothesis that HIV-1 infection and cigarette smoking act in concert to create a pattern of AM gene expression indicative of up-regulated expression of genes relevant to the pathogenesis of emphysema and that these changes are in excess of, or in addition to, that induced by smoking or HIV-1 alone. Aim 2. Based on the knowledge that HIV-1 infection is associated with elevated systemic and lung levels of tumor necrosis factor-a (TNF-a) and interferon-Y (IFN-v), and that expression of TNF-a or IFN-v in the lungs of experimental animals is associated with the development of emphysema, we will examine the hypothesis that the exaggerated program of emphysema-related mediators expressed by AM of HIV-1 + smokers is linked to the overexpression of TNF-a and/or IFN-y in the lung. Aim 3. To examine the hypothesis that while HAART therapy effectively suppresses replication of HIV-1 in the AM, it does not entirely suppress the pattern of gene expression of the AM relevant to the pathogenesis of emphysema, and that the persistence of the subset of up-regulated genes in the AM is linked to TNF-a or INF-v in the milieu of the alveolus. [unreadable] [unreadable] [unreadable]